Cardio-facio-cutaneous syndrome (CFC) is a sporadic, complex developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, growth deficiency,
hypotonia, and developmental delay. CFC is caused by alteration of activity through the
mitogen-activated protein kinase (MAPK) pathway due to heterogeneous de novo germline mutations in B-Raf
mutant proteins, MEK1 and MEK2. Approximately 75% of individuals with CFC have mutations in BRAF. In vitro functional studies demonstrate that many of these mutations confer increase activity upon the
mutant protein as compared to the wildtype
protein. However, as is seen
cancer, some of the B-Raf
mutant proteins are
kinase impaired. Western blot analyses corroborate
kinase assays as determined by
mutant proteins phosphorylating downstream effectors
MEK and ERK. Approximately 25% of individuals with CFC have mutations in either MEK1 or MEK2 that lead to increased
MEK kinase activity as judged by increased phosphorylation of its downstream effector ERK. Unlike BRAF, no somatic mutations have ever been identified in
MEK genes. The identification of novel germline BRAF and
MEK mutations in CFC will help understand the pathophysiology of this syndrome. Furthermore, it will also provide insight to the normal function of B-Raf and
MEK, and contribute to the knowledge of the role of the MAPK pathway in
cancer. Since the MAPK pathway has been studied intensively in the context of
cancer, numerous
therapeutics that specifically target this pathway may merit investigation in this population of patients.